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Lactate AND Metformin

Giulio Calza, Elisabeth Nyberg, Matias Mäkinen, Rabah Soliymani, Annunziata Cascone, Dan Lindholm, Emanuele Barborini, Marc Baumann, Maciej Lalowski, Ove Eriksson
Metformin is the first line drug for type 2 diabetes but its molecular mechanisms remain unclear. Here, we have studied the acute effect of a therapeutically relevant intrahepatic concentration of metformin on glucose production from lactate. We selected the perfused rat liver as experimental system since it enables the complete control of drug dosage. We used MALDI (matrix-assisted laser desorption/ionization) mass spectrometry imaging to estimate the concentration of metformin in the livers and we measured the concentration of glucose in the effluent medium under basal conditions and following lactate addition...
2018: Frontiers in Pharmacology
Dehua Tang, Lei Xu, Mingming Zhang, Robert Gregory Dorfman, Yida Pan, Qian Zhou, Lixing Zhou, Yuming Wang, Yang Li, Yuyao Yin, Lei Wang, Xiaoping Zou
Cholangiocarcinoma (CCA) is a highly lethal malignancy with an often late diagnosis and consequent poor prognosis. Chemotherapy is the only therapeutic strategy for most patients. Compared to normal cells, tumor cells preferentially metabolize glucose to lactate, even in aerobic conditions. Such metabolic alterations not only support the growth and invasion of tumor cells, but also promote their chemoresistance. The purpose of our study was to explore the role of metformin in regulating the metabolism of CCA, as well as to investigate whether metformin could act as a chemosensitizer of the HDAC3 inhibitor BG45, and therefore have potential for the treatment of CCA...
February 20, 2018: Oncology Reports
A Cetinkaya, D Avci, A Erden, O Akca, O Ozer, U Kalan, A I Gunal
Introduction: This study has been performed for the purpose of researching the complications occurred at patients who took metformin overdose in an attempt to suicide. None of the patients has the diagnosis of diabetes mellitus and never used metformin. Materials and Methods: This retrospective cross-sectional study was carried out with 21 patients who has neither diagnosed diabetes mellitus nor taken metformin for suicide before. Results: It was observed that there is a moderate, negative (r = -0...
February 2018: Nigerian Journal of Clinical Practice
L McCreight, T B Stage, P Connelly, M Lonergan, F Nielsen, C Prehn, J Adamski, K Brosen, E R Pearson
AIMS: Metformin intolerance symptoms are gastrointestinal in nature, but the underlying mechanism is poorly understood. The aim of this study was to assess potential causes of metformin intolerance including: altered metformin uptake from the intestine; increased anaerobic glucose utilisation and subsequent lactate production; altered serotonin uptake; and altered bile acid pool. METHODS: This pharmacokinetic study recruited ten severely intolerant and ten tolerant individuals matched for age, sex and BMI...
February 19, 2018: Diabetes, Obesity & Metabolism
Lauren Krowl, Hassan Al-Khalisy, Pratibha Kaul
A new diagnostic paradigm has been proposed to better categorize causes of Metformin-Associated Lactic Acidosis (MALA). The diagnostic criteria defines a link between Metformin and lactic acidosis if lactate is >5mmol/L, Ph<7.35 and Metformin assay >5mg/L. Metformin assays are not readily available in emergency departments including nationwide Veteran's Affairs Hospitals; thereby making this proposed classification tool difficult to use in today's clinical practice. We describe a case report of a 45-year-old male, who took twice the amount of Metformin prescribed and presented with Metformin-induced lactic acidosis...
February 15, 2018: American Journal of Emergency Medicine
Takehide Umeda, Taro Minami, Keith Bartolomei, Eleanor Summerhill
A 54-year-old woman with type 2 diabetes mellitus, hypertension, and peripheral vascular disease developed life-threatening lactic acidosis during treatment with metformin for type 2 diabetes. The woman received metformin at 1000 mg orally twice a day for type 2 diabetes. She presented to our emergency department with a 3-day history of severe watery diarrhea, nausea, and vomiting. Her grandson whom she cared for had gastroenteritis several days prior to the onset of her symptoms. She was confused and hypotensive with a blood pressure of 70/39 mmHg...
February 9, 2018: Drug Safety—Case Reports
Dannielle DeWaal, Veronique Nogueira, Alexander R Terry, Krushna C Patra, Sang-Min Jeon, Grace Guzman, Jennifer Au, Christopher P Long, Maciek R Antoniewicz, Nissim Hay
Hepatocellular carcinoma (HCC) cells are metabolically distinct from normal hepatocytes by expressing the high-affinity hexokinase (HK2) and suppressing glucokinase (GCK). This is exploited to selectively target HCC. Hepatic HK2 deletion inhibits tumor incidence in a mouse model of hepatocarcinogenesis. Silencing HK2 in human HCC cells inhibits tumorigenesis and increases cell death, which cannot be restored by GCK or mitochondrial binding deficient HK2. Upon HK2 silencing, glucose flux to pyruvate and lactate is inhibited, but TCA fluxes are maintained...
January 31, 2018: Nature Communications
Ajith Munasinghe Dissanayake, Mark Christopher Wheldon, Jafar Ahmed, Christopher John Hood
Introduction: Metformin use in advanced chronic kidney disease is controversial. This study sought to examine the pharmacokinetics, safety, and efficacy of low-dose metformin in patients with type 2 diabetes and stage 4 chronic kidney disease. Methods: In this open-label, phase I trial, 3 consecutive cohorts (1, 2, and 3) of 6 patients each were recruited to receive 250-, 500-, or 1000-mg once-daily doses of metformin, respectively. All patients underwent a first-dose pharmacokinetic profile and weekly trough metformin concentrations for the duration of 4 weeks of daily therapy...
July 2017: KI Reports
Jean-Daniel Lalau, Farshad Kajbaf, Youssef Bennis, Anne-Sophie Hurtel-Lemaire, Frans Belpaire, Marc E De Broe
OBJECTIVE: This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies. RESEARCH DESIGN AND METHODS: Three complementary studies were performed: 1 ) a dose-finding study in CKD stages 1-5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase; 2 ) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA 1c concentrations monitored monthly; and 3 ) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD3A, 3B, and 4...
January 5, 2018: Diabetes Care
J Wagner, V Luber, J F Lock, U A Dietz, S Lichthardt, N Matthes, K Krajinovic, C-T Germer, S Knop, A Wiegering
Diabetes mellitus is the most frequent metabolic disorder in the western world with a prevalence of 3% in adults under 65 years of age and 14.3% in adults over 65 years of age. Due to the increasing age of our population, the number of patients taking oral antidiabetic drugs has increased. Thus, operating physicians must make a risk-adapted decision whether the medication can be continued perioperatively or if certain drugs must be paused, and if so, with what risks. Operative interventions can lead to a number of metabolic shifts, which change the normal glucose metabolism...
December 19, 2017: Der Chirurg; Zeitschrift Für Alle Gebiete der Operativen Medizen
Sebastien Jochmans, Jean-Emmanuel Alphonsine, Jonathan Chelly, Ly Van Phach Vong, Oumar Sy, Nathalie Rolin, Olivier Ellrodt, Mehran Monchi, Christophe Vinsonneau
BACKGROUND: Impact of metformin exposure before ICU stay remains controversial. Metformin is thought to induce lactic acidosis and haemodynamic instability but may reduce ICU mortality. We evaluated its influence on outcome in diabetic patients admitted in the ICU and then compared two different populations based on the presence of septic shock. METHODS: We conducted a retrospective cohort study in a 24-bed French ICU between October 2010 and December 2013, including all ICU-admitted diabetic patients...
December 2, 2017: Annals of Intensive Care
Zheng-Wei Lee, Xin-Yi Teo, Zhi J Song, Dawn S Nin, Wisna Novera, Bok A Choo, Brian W Dymock, Philip K Moore, Ruby Y-J Huang, Lih-Wen Deng
Slow and continuous release of H2 S by GYY4137 has previously been demonstrated to kill cancer cells by increasing glycolysis and impairing anion exchanger and sodium/proton exchanger activity. This action is specific for cancer cells. The resulting lactate overproduction and defective pH homeostasis bring about intracellular acidification-induced cancer cell death. The present study investigated the potency of H2 S released by GYY4137 against invasive and radio- as well as chemo-resistant cancers, known to be glycolytically active...
2017: Frontiers in Pharmacology
Yi-Chao Chai, Guo-Xin Dang, Hai-Qi He, Jian-Hua Shi, Hong-Ke Zhang, Rui-Tao Zhang, Bo Wang, Liang-Shuo Hu, Yi Lv
AIM: To compare the effect of University of Wisconsin (UW) solution with or without metformin, an AMP-activated protein kinase (AMPK) activator, for preserving standard and marginal liver grafts of young and aged rats ex vivo by hypothermic machine perfusion (HMP). METHODS: Eighteen young (4 mo old) and 18 aged (17 mo old) healthy male SD rats were selected and randomly divided into three groups: control group, UW solution perfusion group (UWP), and UW solution with metformin perfusion group (MUWP)...
October 28, 2017: World Journal of Gastroenterology: WJG
M Manders, M van Luin, C Kramers, F H Bosch
Metformin-associated lactic acidosis (MALA) is a rare but potentially fatal condition that can easily be avoided. As metformin is known to facilitate the production of lactate, predisposing factors can accelerate this process. In situations of infection or dehydration, metformin can accumulate due to kidney failure, hereby increasing the risk of MALA. Despite controversy in the literature about the presence of a relationship between metformin and lactic acidosis, the severity of the condition is cause for concern and allows for preventive measurements...
2017: Nederlands Tijdschrift Voor Geneeskunde
Xuemei Lv, Qian Ren, Lingli Zhou, Yanyan Geng, Jia Song, A Mina, Basang Puchi, Senlin Yang, Shuyou Meng, Lihui Yang
Background In the general population, the absolute risk of lactic acidosis in patients treated with metformin appears to be low. However, in the Tibetan plateau, an extreme oxygen-deficient environment, there are no data available concerning the safety of metformin. The aim of our study is to assess the safety of metformin in people of the plateau area. Methods We conducted an observational cross-sectional study in Tibet. All the 166 subjects were divided into two groups: T2DM+metformin group and T2DM group...
November 8, 2017: Experimental and Clinical Endocrinology & Diabetes
Wo-Lin Hou, Jun Yin, Miriayi Alimujiang, Xue-Ying Yu, Li-Gen Ai, Yu-Qian Bao, Fang Liu, Wei-Ping Jia
Accumulating evidences showed metformin and berberine, well-known glucose-lowering agents, were able to inhibit mitochondrial electron transport chain at complex I. In this study, we aimed to explore the antihyperglycaemic effect of complex I inhibition. Rotenone, amobarbital and gene silence of NDUFA13 were used to inhibit complex I. Intraperitoneal glucose tolerance test and insulin tolerance test were performed in db/db mice. Lactate release and glucose consumption were measured to investigate glucose metabolism in HepG2 hepatocytes and C2C12 myotubes...
November 6, 2017: Journal of Cellular and Molecular Medicine
Laura N Deden, Edo O Aarts, Stephanie C W Aelfers, Marcel M G J van Borren, Ignace M C Janssen, Frits J Berends, Hans de Boer
BACKGROUND: Pharmacokinetic data suggest that the risk of metformin-associated lactic acidosis (MALA) may be increased after Roux-en-Y gastric bypass (RYGB) surgery. The aim of this study was to examine the impact of metformin on plasma lactate levels before and after RYGB surgery. METHODS: Retrospective study of plasma lactate levels before and 3 months after RYGB surgery in patients with type 2 diabetes mellitus (T2DM) not using metformin (MET-0, N = 58), on a stable dose (MET-S, N = 138), or on a decreasing dose (MET-D, N = 85) of metformin...
October 23, 2017: Obesity Surgery
Shuangxin Liu, Lixia Xu, Jianchao Ma, Renwei Huang, Ting Lin, Zhuo Li, Huabang Liang, Sijia Li, Ruizhao Li, Li Zhang, Yiming Tao, Zhilian Li, Yuanhan Chen, Zhiming Ye, Bin Zhang, Wenjian Wang, Houqing Xiao, Xinling Liang, Wei Shi
We present the case of a 42-year-old female patient who attempted suicide by taking approximately 100 tablets of metformin (500 mg). Laboratory tests revealed severe lactic acidosis with lactate levels of 24 mmol/L and pH of 7.09. The patient was treated with high-volume continuous venovenous hemodiafiltration (CVVH) and resin-sorbent hemoperfusion. Metformin concentrations were measured by high-performance liquid chromatography during CVVH and hemoperfusion treatment. Before extracorporeal treatment, the plasma metformin concentration was 208...
October 5, 2017: Journal of Diabetes Investigation
A H Hulst, J A W Polderman, E Ouweneel, A J Pijl, M W Hollmann, J H DeVries, B Preckel, J Hermanides
Historically, metformin was withheld before surgery for fear of metformin-associated lactic acidosis. Currently, however, this risk is deemed to be low and guidelines have moved towards the continuation of metformin. We hypothesized that continuing metformin peri-operatively would lower postoperative serum glucose level without an effect on plasma lactate levels. We performed a single-blind multicentre randomized controlled trial in people with type 2 diabetes mellitus scheduled for non-cardiac surgery and continued (MF+ group) or withheld (MF- group) metformin before surgery...
September 20, 2017: Diabetes, Obesity & Metabolism
Haiyun Qi, Per M Nielsen, Marie Schroeder, Lotte B Bertelsen, Fredrik Palm, Christoffer Laustsen
AIMS/HYPOTHESIS: Metformin inhibits hepatic mitochondrial glycerol phosphate dehydrogenase, thereby increasing cytosolic lactate and suppressing gluconeogenesis flux in the liver. This inhibition alters cytosolic and mitochondrial reduction-oxidation (redox) potential, which has been reported to protect organ function in several disease states including diabetes. In this study, we investigated the acute metabolic and functional changes induced by metformin in the kidneys of both healthy and insulinopenic Wistar rats used as a model of diabetes...
September 21, 2017: Diabetologia
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